African Americans have a four-fold higher incidence rate of end stage renal disease (ESRD) relative to European Americans. This racial disparity is not fully accounted for by differences in socioeconomic status, access to medical care or control of hypertension. Additionally, familial aggregation studies indicate a strong genetic component to predisposition to ESRD. These observations suggest that an inherited susceptibility to ESRD is present. While diabetes associated ESRD is the leading individual cause of ESRD, it should be noted that more than half of all ESRD cases are not associated with diabetes. The goal of this proposal is to identify genes associated with non-diabetic ESRD in African Americans. A previous genome-wide scan of African Americans with non-diabetic ESRD showed evidence for linkage at three chromosomal regions, Ch13q13.1, Ch13q33.3, and Ch1q25.1. These regions will be investigated as part of the following Specific Aims. 1. Candidate genes in these regions will be selected based on known functional activity, subjected to high density SNP analysis, and tested for association with non-diabetic ESRD in a case-control design. 2. A dense SNP map of the most promising region, Ch13q33.3, will be completed to refine linkage peaks and prioritize regions into haplotype blocks for positional cloning of candidate genes. 3. Positional candidate genes in the haplotype blocks defined by Specific Aim 2 will be identified and tested for association with ESRD using high density SNP analysis. Associated regions will be sequenced to determine the specific genetic polymorphism contributing to ESRD susceptibility. The completion of these Specific Aims will result in the identification of one or more genes that are associated with susceptibility to non-diabetic ESRD in African Americans. The Medicare costs associated with ESRD are substantial and the personal cost to patients and their families is immeasurable. Despite the increased risk of non-diabetic ESRD among African Americans, limited research has been carried out targeted at understanding genetic susceptibility to non-diabetic ESRD. This research proposal is aimed at specifically identifying genes that are associated with susceptibility to non-diabetic ESRD. The results of this study will enable early identification of at-risk patients and contribute to our understanding of the pathophysiology of ESRD.